Functions of the Nuclear Receptor SHP

核受体 SHP 的功能

• 批准号: 7030908
• 负责人: DAVID D MOORE
• 金额: $ 44.12万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7030908
• 关键词: adipose tissue; diabetes risk; fats; gene deletion mutation; gene expression; genetic models; genetically modified animals; hypertension; insulin sensitivity /resistance; laboratory mouse; metabolic syndrome; model design /development; nuclear receptors; obesity; polymerase chain reaction; protein structure function; southern blotting

DESCRIPTION (provided by applicant): The current obesity epidemic is driving a dramatic increase in the metabolic syndrome (syndrome X), a constellation of disorders that includes diabetes, dyslipidemias and hypertension. This proposal takes a broad approach to understanding the molecular mechanisms that account for effects of the orphan receptor SHP in most, if not all of the primary aspects of this syndrome. When subjected to appropriate stresses, SHP null mice exhibit a number of intriguing phenotypes including loss of negative feedback regulation of bile acid biosynthesis, loss of an acute inhibitory effect of bile acids on hepatic triglyceride production, resistance to diet induced obesity, increased insulin sensitivity, and resistance to the combined hypertensive effects of increased aldosterone and renin and decreased expression of the atrial and B-type natriuretic peptide genes. The overall goal of this proposal is to characterize the physiologic effects of the loss of SHP and define the molecular basis for these effects. The specific aims are to: 1) Generate appropriate specific knockout and transgenic gain of function models to facilitate studies of tissue specific effects of SHP. 2) Characterize the role of increased brown adipose tissue activity in the obesity resistance of the SHP deficient mice and define the molecular basis for this increased activity. 3) Characterize the physiologic basis for the increased insulin sensitivity of the SHP-/- mice and identify molecular mechanisms that contribute to this effect. 4) Characterize the basis for the increased activity of multiple hypertensive pathways in the SHP knockouts and their resistance to the effects of these pathways. We believe that identifying the specific mechanisms that account for the effects of the loss of SHP function will provide new insights into the interlocking mechanisms that result in metabolic homeostasis and new approaches to addressing metabolic diseases.

描述（由申请人提供）：目前肥胖症的流行正在推动代谢综合征（X综合征）的急剧增加，代谢综合征是一系列疾病，包括糖尿病、血脂异常和高血压。这项建议采取了广泛的方法来理解的分子机制，占孤儿受体SHP的影响，在大多数，如果不是所有的主要方面，这种综合征。当经受适当的应激时，SHP缺失小鼠表现出许多有趣的表型，包括胆汁酸生物合成的负反馈调节的丧失、胆汁酸对肝甘油三酯产生的急性抑制作用的丧失、对饮食诱导的肥胖的抗性、增加的胰岛素敏感性、以及对醛固酮和肾素增加以及心房肌和B-受体表达减少的联合高血压效应的抵抗。型利钠肽基因。该提案的总体目标是表征SHP丧失的生理效应，并确定这些效应的分子基础。具体目标是：1）建立合适的特异性敲除和转基因获得功能模型，以便于研究SHP的组织特异性效应。2)表征增加的棕色脂肪组织活性在SHP缺陷小鼠的肥胖抵抗中的作用，并定义这种增加的活性的分子基础。3)描述SHP-/-小鼠胰岛素敏感性增加的生理基础，并确定导致这种效应的分子机制。4)表征SHP敲除中多种高血压途径活性增加的基础及其对这些途径作用的抗性。我们相信，确定SHP功能丧失的具体机制将为导致代谢稳态的联锁机制提供新的见解，并为解决代谢疾病提供新的方法。